Angela Koh

Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success

Background. Successful islet transplantation can result in insulin independence in many patients with type 1 diabetes mellitus, but it often requires more than one islet infusion. The ability to achieve insulin independence with a single donor is an important goal in clinical islet transplantation due to the limited organ supply. Methods. We examined factors that may be associated with insulin independence after islet transplantation with islets from a single donor, using univariate and multivariate analysis. Results. Thirteen of 85 (15.3%) achieved insulin independence after single-donor islet transplantation. Using multivariate analysis, only the use of insulin and heparin infusions peritransplant was a significant factor associated with insulin independence, with an adjusted odds ratio of 8.6 (95% confidence interval 2.0-37.0). Patients who had received insulin and heparin infusions peritransplant had greater indices of islet engraftment and a greater reduction in insulin use (80.1%±4.3% vs. 54.2%±2.8%, P<0.001) even if insulin independence was not achieved. Conclusions. Peritransplant intensive insulin and heparin enhances islet transplantation outcomes likely related in part to mitigation of the effects of the instant blood-mediated inflammatory reaction, combined with islet rest and avoidance of inflammation. It would be important to further investigate the effects of peritransplant insulin and heparin infusions on islet engraftment.

Histologic graft assessment after clinical islet transplantation.

Background. An accurate monitoring would help understanding the fate of islet grafts after transplantation. Methods. This work assessed the feasibility of needle biopsy monitoring after intraportal islet transplantation (n=16), and islet graft morphology was studied with the addition of autopsy samples (n=2). Pancreas autopsy samples from two nondiabetic individuals were used as control. Results. Islet tissue was found in five needle samples (31%). Sampling success was related to size (100% sampling for the four biopsies of 1.8 cm in length or higher, P≤0.01). Mild liver abnormalities included localized steatosis (n=8), mild nodular regenerative hyperplasia and mild portal venopathy (n=3), and hepatocyte swelling (n=2). Endocrine cell composition and distribution were similar between islet grafts and normal islets within the native pancreas. There was no or minimal immune cell infiltrate in patients on and off exogenous insulin, including two patients with ongoing negative metabolic events (increasing HbA1c or insulin requirement). The infiltrate was mainly composed of CD4- and CD8-positive cells. Conclusion. This study demonstrates that needle biopsy is feasible after clinical islet transplantation but with a limited practical value because of its low islet sampling rate using current sampling and analysis methods. Both biopsy and autopsy samples demonstrated the well-preserved islet endocrine composition after transplantation and the presence of focal areas of steatosis. Islet grafts showed no or minimal immune cell infiltration, even in the case of ongoing islet loss. On the basis of the findings, possible reasons for allograft islet loss are discussed.

Portal Vein Thrombosis Is a Potentially Preventable Complication in Clinical Islet Transplantation

Percutaneous transhepatic portal access avoids surgery but is rarely associated with bleeding or portal venous thrombosis (PVT). We herein report our large, single‐center experience of percutaneous islet implantation and evaluate risk factors of PVT and graft function. Prospective data were collected on 268 intraportal islet transplants (122 subjects). A portal venous Doppler ultrasound was obtained on Days 1 and 7 posttransplant. Therapeutic heparinization, complete ablation of the portal catheter tract with Avitene paste and limiting packed cell volume (PCV) to <5 mL completely prevented any portal thrombosis in the most recent 101 islet transplant procedures over the past 5 years. In the previous cumulative experience, partial thrombosis did not affect islet function. Standard liver volume correlated negatively (r =−0.257, p < 0.001) and PCV correlated positively with portal pressure rise (r = 0.463, p < 0.001). Overall, partial portal thrombosis occurred after 10 procedures (overall incidence 3.7%, most recent 101 patient incidence 0%). There were no cases of complete thrombosis and no patient developed sequelae of portal hypertension. In conclusion, portal thrombosis is a preventable complication in clinical islet transplantation, provided therapeutic anticoagulation is maintained and PCV is limited to <5 mL.

Late Cytomegalovirus Transmission and Impact of T-Depletion in Clinical Islet Transplantation

The epidemiology of cytomegalovirus infection (CMV) in islet transplantation (IT) is not well defined. This study defines incidence, transmission and clinical sequelae of CMV reactivation or disease in 121 patients receiving 266 islet infusions at a single institution. The donor (D)/recipient (R) serostatus was D+/R– 31.2%, D+/R+ 26.3%, D–/R+ 13.2% and D–/R– 29.3%. CMV prophylaxis with oral ganciclovir/valganciclovir was given in 68%. CMV infection occurred in 14/121 patients (11.6%); six had asymptomatic seroconversion and eight others had positive viremia (six asymptomatic and two with CMV febrile symptoms). Median peak viral loads were 1755 copies/mL (range 625–9 100 000). Risk factors for viremia included lymphocyte depletion (thymoglobulin or alemtuzumab, p < 0.001). Viremia was more common in D+/R+ versus D+/R– (p = 0.12), occurring mostly late after transplant (median 306 days). Presumed transmission from IT occurred in 8/83 of D+/R– procedures (9.6%). Of the two cases of CMV disease, one resulted from islet transmission from a CMV positive donor (D+/R–); the other was due to de novo exogenous infection (D–/R–). Therefore, CMV transmission presents rarely after IT and with low incidence compared to solid organ transplantation, but occurs late posttransplant. The use of lymphocyte depleting therapies is a primary risk factor.

High prevalence of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus after clinical islet transplantation

We encountered an unexpectedly high rate of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus following islet transplantation. The goal of this retrospective chart review was to determine the frequency of ovarian cysts found on pelvic ultrasound examinations of female islet transplant recipients and to look for potential causal factors. Fifty‐seven women with a median age of 42.5 years underwent islet transplantation at the University of Alberta. Ovarian cysts were found in 31 out of 44 (70.5%) premenopausal and two out of 13 (15.4%) postmenopausal women (P = 0.001). No women using combined oral contraception developed ovarian cysts. Eight women required surgery; in four women undergoing cystectomy or unilateral oophorectomy, ovarian cysts recurred. Sirolimus withdrawal was associated with a reduction in cyst size and resolution of cysts in 80% of subjects. The risk of ovarian cysts should be discussed with female islet transplant candidates and pelvic ultrasounds performed routinely post‐transplant.

Supplemental islet infusions restore insulin independence after graft dysfunction in islet transplant recipients.

Background. The ability of supplemental islet infusions (SII) to restore insulin independence in islet transplant recipients with graft dysfunction has been attributed to the coadministration of exenatide. However, improving islet transplant outcomes could explain the success of SII. We aimed to determine the effect on islet graft function and insulin independence of SII using these new protocols, without the use of exenatide. Methods. Seventeen islet transplant recipients underwent SIIs after developing graft dysfunction requiring insulin use. For induction therapy, four subjects received daclizumab induction therapy, whereas 13 subjects received thymoglobulin and etanercept. Maintenance immunosuppression consisted of sirolimus+tacrolimus or tacrolimus+cellcept. Results. SII was performed 49.3±4.8 months (mean±SEM) after the preceding islet transplant. Subjects received significantly lower islet mass with their SII compared with initial transplant(s) (6076±492 vs. 9071±796 IEQ/kg; P=0.003). Fifteen of the 17 subjects (88.2%) became insulin independent 2.4±0.5 months after SII. Insulin-independent duration after SII exceeded that of the initial transplant(s) (24.8±2.2 vs. 14.2±2.6 months by Kaplan-Meier analysis, P=0.009). Subjects show improved glycemic control after SII (HbA1c 7.0%±0.2% pre-SII vs. 6.1%±0.2% post-SII, P=0.005) and did not become immunosensitized. Conclusion. Using current protocols, SII in the absence of exenatide results in impressive insulin-independence rates and the durability of insulin independence seems to be promising. However, a beneficial effect of exenatide should not be discounted until tested in randomized controlled studies.

Three cases of alopecia following clinical islet transplantation.

Successful clinical islet allotransplantation requires control of both allo‐ and autoimmunity by using immunosuppressant drugs which have a number of side effects. The development of the autoimmune condition alopecia areata following successful islet transplantation is therefore unexpected. Three cases of alopecia affecting female islet transplant recipients are described. In all cases, alopecia developed approximately 7 years after initial transplant. All had received daclizumab, sirolimus and tacrolimus with their initial transplants, but all were receiving a combination of tacrolimus and mycophenolate mofetil at the time alopecia developed. Two subjects had received thymoglobulin for a subsequent islet infusion and prior to the onset of alopecia. The progression of alopecia has been halted or reversed in all cases. Tacrolimus has been continued in two cases (one as monotherapy) while cyclosporine was used in place of tacrolimus in the third case. These three cases represent a crude incidence of <2.5% over 5 years compared with a prevalence of alopecia in islet transplant candidates (pretransplant) of <1%. Although alopecia might be expected in a proportion of individuals with type 1 diabetes, the risk may be increased after islet transplantation, and may be associated with the use of anti‐TNF drugs, lymphodepleting antibodies or higher dose tacrolimus.

ALEMTUZUMAB INDUCTION AND TAC/MMF MAINTENANCE SUBSTANTIALLY IMPROVES LONG TERM INSULIN INDEPENDENCE RATES AFTER CLINICAL ISLET TRANSPLANTATION, AND STRONGLY SUPPRESSES BOTH AUTO AND ALLOREACTIVITY: 2026

A.M..J. Shapiro1, C. Toso2, A. Koh3, S.R. Calne4, T. Kin5, D. O’Gorman6, A. Malcolm3, P. Dinyari3, S. Imes3, R. Owen3, N.M. Kneteman7, D. Bigam8, P. Senior9, B. Roep10 1Surgery, University of Alberta, Edmonton/AB/CANADA, 2Visceral And Transplantation Surgery, Geneva University Hospitals, Geneva/ SWITZERLAND, 3Surgery, University of Alberta, Edmonton/ CANADA, 4Surgery, University of Cambridge, CB2 2AS/UNITED KINGDOM, 5Clinical Islet Transplant Program, University of Alberta, Edmonton/CANADA, 6Clincal Islet Labroatory, Alberta Helath Sevices, Edmonton/AB/CANADA, 7Department Of Surgery, University of Alberta, Edmonton/AB/CANADA, 8, University of Alberta, Edmonton/CANADA, 9Clincial Islet Transplant Program, University of Alberta, Edmonton/AB/CANADA, 10Dept Immunohaematology And Blood Transfusion, Leiden University Medical Center, NL-233ZA/ NETHERLANDS

Islets isolated from donors with elevated HbA1c can be successfully transplanted.

Clinical islet transplantation is limited by the availability of donor organs. We report two cases where islets were isolated from donors with elevated HbA1c (6.3% and 7.9%). Islet isolation yield was adequate in both cases (521,350 and 497,472 islet equivalents, respectively). Islet graft analyses revealed a decreased proportion of beta cells (21.6%) and an increase in alpha cells (51.0%) in the donor with the higher HbA1c, although graft characteristics of the other donor were similar to donors with normal HbA1c. Both islet preparations were transplanted into type 1 diabetes recipients with brittle diabetes. One recipient has remained insulin independent for 4 years to date with good glycemic control. The other recipient who received islets from the donor with the higher HbA1c had a 56% reduction in insulin requirement after transplant. Pancreases from donors with mild hyperglycemia may be a source of islets that could be considered for clinical islet transplantation.

Sitagliptin plus pantoprazole can restore but not maintain insulin independence after clinical islet transplantation: results of a pilot study.

Resuming insulin use due to waning function is common after islet transplantation. Animal studies suggest that gastrointestinal hormones, including gastrin and incretins may increase β–cell mass. We tested the hypothesis that pantoprazole plus sitagliptin, would restore insulin independence in islet transplant recipients with early graft insufficiency and determined whether this would persist after a 3–month washout.